1. Technical Field
The present invention is related to fragments of human melanotransferrin (p97). In particular, this invention relates to treatment of diseases through the introduction of the melanotransferrin fragment conjugated to a therapeutic or diagnostic agent to a subject.
2. Description of the Related Art
Melanotransferrin (MTf) is a bi-lobed protein belonging to the transferrin (Tf) family of iron binding proteins. It has been demonstrated previously that MTf is able to directly bind and transport iron into mammalian cells independent of Tf and Tf receptor (TfR). Unlike other Tf family members, this molecule exists in two forms in humans, a glycosyl-phosphatidylinositol (GPI)-linked cell surface form and a secreted water-soluble form. Additionally, MTf is also found to be expressed on human brain endothelium where it is hypothesized to transport iron across the blood brain barrier (BBB). The role of MTf in the transfer of iron into the brain was assessed by following both radiolabeled soluble MTf and Tf into the mouse brain during a 24-hour period (Moroo et al., 2003, Demeule et al., 2002). It was determined that soluble MTf does have the ability to transcytose across the blood-brain barrier (BBB) and this transport was more efficient than that of Tf.
Subsequently, it has been demonstrated that soluble MTf could be used as a delivery vehicle of therapeutics into the brain (Karkan et al., 2008). Pharmacokinetics studies on soluble MTf demonstrated that the clearance of MTf from serum was much greater than IgG control, and was rapidly distributed to the tissues relative to IgG control. The transport of soluble MTf into the brain as a percentage of injected dose was significantly greater than IgG during the first hour post injection. The accumulation of soluble MTf in the brain was found to be significantly more than that of IgG during the first 6-hours post injection.
Furthermore, it was shown that soluble MTf is able to deliver iron across the BBB (Moroo et al., 2003), as well as paclitaxel covalently linked to MTf (Karkan et al., 2008). In the same study, while both free-adriamycin and MTf-adriamycin conjugates were able to equally inhibit the subcutaneous growth of gliomas outside of the brain, only MTf-adriamycin conjugates significantly prolonged the survival of animals bearing intracranial gliomas when compared to the free-adriamycin control (Karkan et al., 2008). Taken together, these data suggest soluble MTf as a potential drug delivery tool.
However, an even more efficient transfer molecule for delivering a target agent would be useful for therapeutic and diagnostic purposes. The present invention addresses these and other needs.